Our previous results indicate that HBx contains a functional nuclear export signal motif that utilizes the Ran/Crm1 complex, a component essential in nucleocytoplasmic transport of many cellular and viral proteins. We demonstrated that HBx not only uses but also disrupts Ran/Crm1-dependent activities, presumably to prevent a host antiviral response. This finding implicates the Ran/Crm1 complex in the molecular pathogenesis of hepatitis B virus. Recently, we uncovered a new role of the Ran/Crm1 complex in regulating cellular proteins that control centrosome duplication and mitotic spindle assembly. We revealed nucleophosmin as a novel substrate for Ran/Crm1 to negatively regulate unnecessary centrosome duplication. In addition, we demonstrated a hepatitis B virus / HBx -dependent activation of RanBP1, a Ran-binding protein that is known to destabilize the Ran/Crm1 complex. Elevated RanBP1 is also observed in positive liver tissues and in hepatocellular carcinoma. Increased expression of RanBP1 leads to multipolar spindles and abnormal mitoses. Thus, the combined effects of hepatitis B virus / HBx contribute to chromosome instability. These findings led us to generate a new hypothesis in which the Ran/Crm1 complex serves as the centrosome duplication checkpoint by providing a loading dock mechanism that controls cellular homeostasis, and the disruption of this complex may result in genomic instability, which may be an early step in viral hepatitis-mediated hepatocarcinogenesis. In addition to HBx, recently we have completed a pilot study by determining hepatitis C virus core-related gene expression profiles in B lymphocytes. We found that hepatitis C virus core may evict immunity by selectively suppressing genes involved in antigen presentation. These studies are useful in dissecting viral activities that are essential in hepatocarcinogenesis. Furthermore, we have conducted molecular profiling studies to compare the gene expression changes in primary human hepatocytes infected with adenoviruses harboring HBx or hepatitis C virus structural or non-structural genes (p21CORE, NS3 or NS5A). We also compared these gene expression profiles to those obtained from hepatitis C virus -infected liver samples from chronic liver disease patients and hepatitis C virus -related hepatocellular carcinoma. We found that hepatitis C virus -related proteins largely induce unique genes when compared to HBx. In particular, interferon-inducible gene 27 was highly expressed in hepatitis C virus or core infected hepatocytes and hepatitis C virus -related chronic liver disease or hepatocellular carcinoma, but was less significantly expressed in HBx infected hepatocytes or hepatitis B virus-related chronic liver disease or hepatocellular carcinoma, indicating that interferon-inducible gene 27 may play a role in hepatitis C virus -mediated hepatocellular carcinoma. In conclusion, our results suggest that hepatitis B virus and hepatitis C virus promote hepatocellular carcinoma development mainly through different mechanisms.Our previous results indicate that HBx contains a functional nuclear export signal motif that utilizes the Ran/Crm1 complex, a component essential in nucleocytoplasmic transport of many cellular and viral proteins. We demonstrated that HBx not only uses but also disrupts Ran/Crm1-dependent activities, presumably to prevent a host antiviral response. This finding implicates the Ran/Crm1 complex in the molecular pathogenesis of hepatitis B virus. Recently, we uncovered a new role of the Ran/Crm1 complex in regulating cellular proteins that control centrosome duplication and mitotic spindle assembly. We revealed nucleophosmin as a novel substrate for Ran/Crm1 to negatively regulate unnecessary centrosome duplication. In addition, we demonstrated a hepatitis B virus / HBx -dependent activation of RanBP1, a Ran-binding protein that is known to destabilize the Ran/Crm1 complex. Elevated RanBP1 is also observed in positive liver tissues and in hepatocellular carcinoma. Increased expression of RanBP1 leads to multipolar spindles and abnormal mitoses. Thus, the combined effects of hepatitis B virus / HBx contribute to chromosome instability. These findings led us to generate a new hypothesis in which the Ran/Crm1 complex serves as the centrosome duplication checkpoint by providing a loading dock mechanism that controls cellular homeostasis, and the disruption of this complex may result in genomic instability, which may be an early step in viral hepatitis-mediated hepatocarcinogenesis. In addition to HBx, recently we have completed a pilot study by determining hepatitis C virus core-related gene expression profiles in B lymphocytes. We found that hepatitis C virus core may evict immunity by selectively suppressing genes involved in antigen presentation. These studies are useful in dissecting viral activities that are essential in hepatocarcinogenesis. Furthermore, we have conducted molecular profiling studies to compare the gene expression changes in primary human hepatocytes infected with adenoviruses harboring HBx or hepatitis C virus structural or non-structural genes (p21CORE, NS3 or NS5A). We also compared these gene expression profiles to those obtained from hepatitis C virus -infected liver samples from chronic liver disease patients and hepatitis C virus -related hepatocellular carcinoma. We found that hepatitis C virus -related proteins largely induce unique genes when compared to HBx. In particular, interferon-inducible gene 27 was highly expressed in hepatitis C virus or core infected hepatocytes and hepatitis C virus -related chronic liver disease or hepatocellular carcinoma, but was less significantly expressed in HBx infected hepatocytes or hepatitis B virus-related chronic liver disease or hepatocellular carcinoma, indicating that interferon-inducible gene 27 may play a role in hepatitis C virus -mediated hepatocellular carcinoma. In conclusion, our results suggest that hepatitis B virus and hepatitis C virus promote hepatocellular carcinoma development mainly through different mechanisms.